Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1)

  • John C. Sparrow
    Department of Biology, University of York, York, YO10 5DD, UK
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  • Kristen J. Nowak
    Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, 4th Floor, ‘A’ Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia

    Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia

    Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
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  • Hayley J. Durling
    Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, 4th Floor, ‘A’ Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia
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  • Alan H. Beggs
    Children's Hospital, Harvard Medical School, Genetics Division, 300 Longwood Avenue, Boston, MA 02115, USA
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  • Carina Wallgren-Pettersson
    Department of Medical Genetics, University of Helsinki and Folkhälsan Institute of Genetics, PO BOX 21 (Haartmaninkatu 3), 00014, Helsinki, Finland
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  • Norma Romero
    Institute de Myologie, INSERM U.523, Hopital de la Salpetriere, 47 Boulevard de l'Hopital, 75013 Paris, France
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  • Ikuya Nonaka
    National Centre Hospital for Mental, Nervous and Muscular Disorders, NCNP, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187, Japan
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  • Nigel G. Laing
    Corresponding author. Tel.: +8-9346-2659; fax: +8-9346-3487
    Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, 4th Floor, ‘A’ Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia

    Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia
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      Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype–phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.


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